期刊
JOURNAL OF CONTROLLED RELEASE
卷 339, 期 -, 页码 297-306出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2021.09.040
关键词
Antitumour; Chemotherapy; SN38; Drug delivery systems; Albumin
资金
- Fundamental Research Funds for the Central Universities
- National Natural Science Foundation of China [22077034]
The novel Mal-glu-SN38 prodrug showed selective delivery of SN38 to tumour sites and enhanced efficacy. With slower plasma clearance, increased drug exposure over time, and enhanced accumulation at the tumour site, Mal-glu-SN38 significantly delayed tumour growth after multiple doses, leading to an impressive reduction or even disappearance of tumours without observable side effects in 67% of mice.
Developing new therapeutic strategies that damage tumour cells without harming normal tissues is among the primary obstacles in chemotherapy. In this study, a novel 13-glucuronidase-sensitive albumin-binding prodrug was designed and synthesized to selectively deliver the drug SN38 to tumour sites and maximize its efficacy. After intravenous administration, the prodrug Mal-glu-SN38 covalently bound to plasma albumin through the Michael addition, enabling it to accumulate in the tumour and release SN38 when triggered by extracellular 13-glucuronidase. Compared to irinotecan, Mal-glu-SN38 displayed a slower plasma clearance and increased drug exposure over time. Moreover, Mal-glu-SN38 caused an increase in tumour-site accumulation of both the albumin-prodrug conjugate and free SN38 released from albumin conjugate when compared with irinotecan. After administration of multiple doses, Mal-glu-SN38 also significantly delayed the tumour growth, resulting in an impressive reduction or even disappearance of tumours (67% of mice cured) without causing any observable side effects.
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